Injectable opioid partial agonist or opioid antagonist microparticle compositions and their use in reducing consumption of abused substances

ABSTRACT

An injectable slow-release partial opioid agonist or opioid antagonist formulation is provided comprising a partial opioid agonist or opioid antagonist in a poly(D,L-lactide) excipient with a small amount of residual ethyl acetate. Upon intramuscular injection of the composition, a partial opioid agonist or opioid antagonist is released in a controlled manner over an extended period of time. The composition finds use in the treatment of heroin addicts and alcoholics to reduce consumption of the abused substances. Of particular interest are the drugs buprenorphine, methadone and naltrexone.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of provisional applicationserial No. 60/151,112, filed Aug. 27, 1999, which disclosure isincorporated herein by reference.

INTRODUCTION BACKGROUND

[0002] The disease of substance abuse remains a scourge on society. Asit becomes more evident that there is a substantial genetic contributionto becoming addicted, helping addicted individuals to terminate theirdependency or at least achieve a level of becoming a functional memberof society, rather than treating substance abuse as a moral issue, hasbecome increasingly accepted policy. Various programs have been put inplace in the public and private sectors. In the private sectors, thereare such organizations as Alcoholics Anonymous and Narcotics Anonymous,which play an important role in psycho-social support. In addition thereare many private clinics which serve to provide both psycho-socialsupport and medicinal support, using the somewhat limited repertoire ofdrugs which are available. In the public arena, there are the extensiveprograms to bring to the attention of young people and parents thehazards of substance abuse and discourage the young people fromembarking on drug use. Also, there are the methadone programs, which areprimarily public supported.

[0003] The number of substance abusing subjects in the United States isquite staggering. There are estimated to be about 15 million people whoabuse alcohol, about 1.3 million who abuse cocaine in its manymanifestations, about 0.8 million who abuse amphetamines and about0.5-0.8 million who abuse heroin, in addition to the use of other drugs,such as the psychedelic drugs. Efforts to reduce the numbers ofscheduled substances and alcohol users have been continuous andrelatively unavailing. Those subjects who have entered programs have hada dismal record of relapse, so that only a small proportion of thepeople who do enter programs and are retained in the programs remainclean long after the completion of the program.

[0004] One significant factor in lack of retention and relapse iscompliance. A repetitive act, such as taking a pill daily, is not asimple matter, even where the subject has no qualms about taking thepill. With the substance abuser, who may have physiological andemotional needs for the abused substance, the sustaining of thetherapeutic routine is substantially more difficult. Therapeutictechniques, which require perseverance on the part of the subject,decrease the likelihood of success of the treatment. It is therefore ofgreat importance to be able to reduce the level of involvement of thesubject where medicinal treatments are involved, particularly treatmentswhich may involve frequent scheduling, monitoring of compliance, andsustaining a particular regimen.

[0005] In order to reduce the vicissitudes of compliance, there havebeen efforts to provide sustained-release methodologies. These haveinvolved pumps, patches, depots and the like. Where the releaseimplement is accessible to the subject, there is always the temptationto remove the implement during a craving episode. This opportunity,which may be an indication of will power, nevertheless, puts the subjectat risk who succumbs to the temptation. By providing for a slow-releasemedicament which is introduced into the body, the temptation is avoidedand the drug is released in accordance with a predetermined scheduleover an arranged period of time. One can have implantable rods which areintroduced surgically or microparticles which are injectable. Rods ormicroparticles can be devised to release the drug over an extendedperiod of time in a controlled manner.

[0006] Microcapsules and microspheres are usually powders consisting ofspherical particles 2 mm or less in diameter, usually 500 μm or less indiameter. If the particles are less than 1 μm, they are often referredto as nanocapsules or nanospheres. For the most part, the differencebetween microcapsules and nanocapsules or the difference betweenmicrospheres and nanospheres is their size.

[0007] A microcapsule or nanocapsule has its encapsulated material(hereinafter referred to as agent) centrally located within a uniquemembrane, usually a polymeric membrane. This membrane may be termed awall-forming membrane, and is usually a polymeric material. Because oftheir internal structure, permeable microcapsules designed forcontrolled-release applications release their agent at a constant rate(zero-order rate of release). Also, impermeable microcapsules can beused for rupture-release applications. A microsphere has its agentdispersed throughout the particle; that is, the internal structure is amatrix of the agent and excipient, usually a polymeric excipient.Usually, controlled-release microspheres release their agent at adeclining rate (first-order). But microspheres can be designed torelease agents at a near zero-order rate. Microspheres tend to be moredifficult to rupture as compared to microcapsules because their internalstructure is stronger. Hereinafter, the term microparticles will includenanospheres, microspheres, microcapsules, nanocapsules, microbubbles(hollow particles), porous microbubbles, nanoparticles, microsponges(porous microspheres) and particles in general.

[0008] Various slow-release microparticles have been developed for avariety of drugs, but very few have been commercialized. There are manyconstraints on a satisfactory slow-release injectable formulation: therelease of the drug must be over an extended period of time; during thetime of treatment, the level of drug maintained in the subject must bean effective level, without reaching any hazardous level; the drug mustbe released slowly without a catastrophic dumping of the drug; thepolymeric excipient used for the microparticles must be biodegradableand biocompatible; any residual chemicals must be below the maximumacceptable level; the microparticles must be small and capable of beingadministered by a syringe with a needle size which is acceptable topatients; the results must be reproducible, which requires that theprocess can be accurately controlled and is not unduly sensitive tominor changes in conditions; the injectable formulation must be sterile;and must have other characteristics which may be general or specific tothe particular medicament. The properties of the microparticles aresensitive to many properties of the drug and excipient, as well as theselection of the process and the conditions under which themicroparticles are prepared and subsequently processed.

[0009] Relevant Literature

[0010] Buprenorphine(N-cyclopropylmethyl-7-[1-(s)-hydroxy-1,2,2-trimethylpropyl]-6,14-endoethano-6,7,8,14-tetrahydronororipavine)is reported as effective in the treatment of opiate addiction usingsublingual administration (U.S. Pat. No. 4,935,428). Nasaladministration of buprenorphine is reported in U.S. Pat. No. 4,464,378.Long-acting drug antagonists are reported in U.S. Pat. Nos. 5,716,631and 5,858,388. The use of buprenorphine for the treatment of drugdependence has been reported in numerous publications. Kuhlman et al.,Addiction 1998 93:549-59; Schottenfeld et al., Arch Gen. Psychiatry1997, 54:713-20; Strain et al., J. Clin. Psychopharmacol 1996, 16:58-67;are illustrative of a few of the reports. The combination ofbuprenorphine and naloxone is reported in O'Connor et al., Ann. InternMed. 1997, 127: 526-30.

[0011] Krantzler, et al., Alcoholism:Clin and Exp Res 1998, 22:1074-1079report the treatment of alcoholics with a slow-release naltrexoneparticle injectable formulation. A number of studies were carried out byReuning's laboratory concerning naltrexone and its use in a slow-releaseform: Reuning, et al., NIDA Re: Monograph Series, Jan. 1976, (4) p43-5;Reuning et al., J. Pharmacokinet Biopharm, August 1983, 11 (4), p369-87;Reuning, et al., Drug Metab Dispos November-December 1989, 17(6) p583-9;MacGregor et al., J. Pharm Pharmacol, January 1983, 35(1) p38-42;Reuning et al., NIDA Res Monograph Series 1980, 28, p172-84. See also,Schwope et al., NIDA Res Monograph Series, 1975, (4), p13-8; Yolles etal., J Pharm Sci February 1975, 64(2) p348-9; Thies, NIDA Res MonographSeries, 1975 (4), p19-20; Schwope et al., NIDA Res Monograph Series,January 1976, 4, p13-18; Chiang et al., Clin Pharmacol Ther November1984 36(5) p704-8; Pitt et al., NIDA Res Monograph Series 1981, 28,p232-53; Chiang et al., Drug Alcohol Depend (SWITZERLAND), September1985, 16 (1) pl-8; Yoburn et al., J. Pharmacol Exp Ther, April 1986, 237(1) p126-130; Cha and Pitt, J. Control Release, 1989, 8(3), p259-265;Yamaguchi and Anderson, J Control Release, 1992, 19(1-3), p299-314.

[0012] The use of naltrexone in the treatment of alcoholism is describedin O'Malley et al., Psychiatric Annals, November 1995, 11, p681-688, aswell as numerous other publications.

[0013] Patents of interest include U.S. Pat. Nos. 4,568,559; 4,623,588;4,897,267; and 5,486,362. U.S. Pat. No. 5,407,609 describes a processapplicable to the process employed in the subject invention.

[0014] The use of polylactide in the preparation of drug-containingmicroparticles is described in Benita et al., J Pharm Sci, December1984, 73(12) p1271-4; Speniehauer et al., ibid, August 1986, 75(8), p750-5; and Nihant et al., October 1994, 11(10), p1479-84.

SUMMARY OF THE INVENTION

[0015] Injectable, slow-release partial opiod agonist and opioidantagonist formulations are provided comprising a therapeuticallyeffective amount of partial opioid agonist or opioid antagonist(hereinafter referred to as drug or agent) released over an extendedperiod of time and an excipient, for example, poly (D,L-lactide)polymer. The microparticles are under 125 μm in diameter and can bereadily injected intramuscularly and provide at least about 0.5 ng/ml ofdrug over the extended period. Different release profiles are obtaineddepending upon the molecular weight of the polymer, the drug and theweight percentage of the drug. The microparticles are prepared bysolvent extraction of a dispersed or dissolved drug polymer solution.Mixtures of microparticles of an agonist drug and an antagonist can beused to diminish any illicit use of the partial opiod agonistmicroparticles.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1 compares the pharmacokinetic profiles for three differentbuprenorphine microparticle formulations after a single administration(25 mg/kg) in dogs.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

[0017] Injectable slow-release partial opiod agonist and/or antagonistformulations are provided for use in the treatment of alcoholics andheroin addicts and such other indications for which partial opiodagonists or antagonists have been found to be efficacious. The partialopioid agonists or antagonists are characterized by having an effectiveplasma level in the range of about 0.5-1 ng/ml, usually 0.75-5 ng/ml,usually not more than about 3 ng/ml. These partial opioid agonistsinclude methadone, buprenorphine, and the like, while the antagonistsinclude naltrexone.

[0018] Small sterilized microparticles are provided which can passthrough a syringe needle and can be administered intramuscularly andremain at the site of injection for an extended period of time whilecontinuously releasing a therapeutically effective amount of the drugfor at least about 28 days. The release profile is found to be sensitiveto the nature and amount of drug in the microparticles, the use of thefree base as compared to the salt, and the inherent viscosity of thepoly(D,L-lactide) excipient. The release profile appears to be lesssensitive to the process conditions under which microparticles wereprepared, the size distribution of the microparticles (as long as thecomposition substantially comprises microparticles in the range of 20 to125 μm) and the amount of solvent retained (so long as the amount ofresidual organic solvent is below 3 weight %).

[0019] The microparticles, as observed by scanning electron microscope(SEM), have the drug dispersed throughout the polymeric excipient. Themicroparticles have less than 3 weight % of ethyl acetate, the solventused in the preparation of the microparticles. The weight percent ofdrug is from 10 to 70 weight %, usually 15 to 65 weight % and varies inrange depending upon the inherent viscosity of the excipient. Theinherent viscosity of the polymeric excipient is in the range of about0.3 to 1.2 dL/g, as measured in chloroform at 30° C. and a concentrationof 0.5 g/dL. Where the polymeric excipient has an inherent viscosity inthe range of about 0.3-0.4 dL/g, the amount of drug will be in the rangeof about 10 to 50 weight %, usually 15 to 50 weight %, while when theinherent viscosity is in the range of about 1.0-1.2 dL/g, usually1.0-1.1 dL/g, the amount of drug will be in the range of about 30 to 70weight %, usually 35 to 65 weight %. For the most part, polymers havinga viscosity in the range of 0.45 to 0.95 dL/g will not be employed,generally only low-molecular weight and higher-molecular weight polymersare used.

[0020] Mixtures of the polymers and microparticles made from suchpolymers or mixtures of such polymers may be used so as to deliver aneffective amount of drug over the desired duration of treatment. Thus,the weight % of two different polymers may range from 1:99 to 99:1, moreusually 10:90 to 90:10, where the lower-molecular-weight polymer will bein lesser amount than the higher-molecular-weight polymer. Similarly,low-drug-loaded, low-molecular-weight excipient microparticles (0.3-0.4dL/g) may be mixed with higher drug loaded, higher molecular weight(1.0-1.2 dL/g) excipient microparticles in weight ratios of 5:95 to95:5, where the lower-molecular-weight excipient microparticles willusually be present in from about 10 to 65 weight %.

[0021] Greater than about 90 weight % of the microparticles will have adiameter in the range of about 20 to 100 μm and less than 5 weight %will have a diameter less than about 10 μm.

[0022] To reduce agglomeration, the microparticles may be coated with anantiagglomerating agent, such as mannitol, which will be employed inless than about 50 weight %, usually less than about 20 weight %, of themicroparticles.

[0023] The microparticles are formulated in an appropriate vehicle toprovide, depending upon the drug, from about 10 mg to 1 g, usually 50 to750 mg of drug, for a single dose. For buprenorphine, the amount willgenerally be in the range of about 20 mg to 1 g, more usually from about20 to 750 mg, while for methadone the amount will be from about 100 to350 mg, more usually from about 150 to 250 mg, and for naltrexone willbe in the range of about 150 to 300 mg. The vehicle may be sterilewater, phosphate buffered saline, or other conventional vehicle foradministering the microparticles. Additives may be present to improvesuspendibility of the microparticles, slow the microparticles settling,and diminish discomfort from the injection. Conveniently, mannitol maybe present in about 2 to 10 weight % of the vehicle, particularly 4 to 7weight % of the vehicle. Other physiologically acceptable additives mayinclude nonionic detergents, e.g. Tween, if present, will be present infrom about 0.05 to 0.2 weight % of vehicle, viscosity enhancing agents,e.g. carboxymethylcellulose, in the range of about 0.1 to 1 weight % ofvehicle, and other conventional additives, as appropriate. The amount ofvehicle will generally be in the range of about 1 to 5 mL, usually 1 to3.5 mL. The microparticles are dispersed in the vehicle immediatelybefore use. Generally, the sterile microparticles will be stored in asterile vial with a septum, where the microparticles may be mixed withthe vehicle and then withdrawn into a syringe.

[0024] The microparticles are prepared by the process substantially asdescribed in U.S. Pat. No. 5,407,609. The process is an emulsion-basedprocess which involves the preparation of an emulsion comprising anaqueous continuous phase (water and a surfactant and/or thickeningagent) and a hydrophobic phase (polymer solvent, polymer and drug).After formation of the emulsion, the polymer solvent is extracted intoan aqueous extraction phase. After a sufficient amount of polymersolvent is extracted to harden the microparticles, the microparticlesare collected on sieves and washed to remove any surfactant remaining onthe surface of the microparticles. The microparticles are then driedwith a nitrogen stream for an extended period, e.g. about 12 hours, thendried in a vacuum oven at room temperature until at least substantiallydry, conveniently for about 3 days.

[0025] A relatively simple apparatus may be employed for the preparationof microparticles. Using storage containers for the different streams,tubing, three-way valves and a homogenizer, the system is readilyassembled. In addition, various monitoring devices may be included, suchas flow meters, temperature monitors, particle size monitors, etc. Theorganic solution is introduced into a first tube connected to a threeway valve, which connects to the aqueous continuous phase and to thehomogenizer. By controlling the rate of flow of the two streams into theline connecting the homogenizer, the ratio of the two streams can becontrolled, as well as the residence time in the homogenizer. Theeffluent from the homogenizer exits through a line which connects to athree-way valve through which the water stream is introduced. Again, therate of flow ratio controls the amount of water to the homogenizereffluent stream. The residence time of the water extraction step iscontrolled by the length of tubing and the rate of flow of the combinedstreams. The microparticles are then segregated by size by passingthrough two or more sieves which eliminates microparticles outside thedesired range.

[0026] For the preparation of the subject microparticles, the dispersedphase contains about 1-10 weight % of the drug and about 20-weight %polymer dispersed or dissolved (hereinafter both are included whenreferring to the polymer in a solvent as dispersed) in ethyl acetate.The continuous phase is an aqueous solution of about 1-10 weight % ofpoly(vinyl alcohol) and contains ethyl acetate at 1 to 7.5 weight %. Theextraction phase is water. Generally, the amount of drug employed willbe from about 10 to 50 weight % in excess of the final drug in themicromicroparticles. Temperatures may be ambient, generally being fromabout 15 to 30° C.

[0027] After the microparticles have been collected and dried they maybe stored at ambient temperatures, particularly in the range of about0-20° C. in an oxygen and water free environment, or divided intoaliquots into appropriate containers and sterilized. Various methods ofsterilization may be employed, gamma irradiation being convenient.

[0028] The primary application for the subject formulations is as anintramuscular injectable, although subcutaneous injections may also beused. The subject will normally be a substance abuser, such as alcoholor heroin, but the subject compositions may be used for otherindications, such as obesity. The appropriate amount of the subjectformulation is directly injected into a convenient site, e.g. gluteus.Thereafter, the subject may be monitored for drug plasma concentrationto ensure that the amount is in the therapeutic range. When the drugplasma concentration falls below the therapeutic range, a subsequentinjection may be made and this process repeated during the treatmentperiod.

[0029] For heroin addicts, the subject will normally be detoxified byany one of a number of different ways, using buprenorphine, clonidine,naltrexone, etc. and checking with naloxone. A response to naloxoneindicates that the subject has not been completely detoxified. Dependingon the drug to be administered, usually a daily regimen of the drug dosewill be made for at least about 3 days and not more than about 2 weeks,to ensure that the subject does not have an adverse reaction to theslow-release detoxification drug. Once it has been established thatthere is no adverse reaction, the depot form of the detoxification drugmay then be administered.

[0030] By having microparticles which have long-term releasingcapability, that is, greater than 14 days, usually greater than about 28days, particularly greater than about 56 days, one can layer theadministration, so that by giving injections in a periodic manner, oneobtains an additive effect. In this manner, smaller doses may beadministered after the first dose, since one continues to obtain releasefrom the prior injected microparticles to which is added the releasefrom the lately administered microparticles, or one can enjoy enhancedlevels of the partial opioid agonist or opioid antagonist withoutincreasing the amount of the microparticles which are administered. Byproviding for microparticles that can continue to release at levels inexcess of 0.5 ng/ml, usually greater than about 1 ng/ml in blood, anddepending on the prescribed plasma levels, usually not exceeding about 5ng/ml, more usually not exceeding about 3 g/ml, for greater than about28 days after injection, preferably at least about 36 days, morepreferably at least about 42 days, there can be a continuous plasmalevel, where the plasma level of the drug may be maintained in thetherapeutic range. In this way, protection is greatly enhanced, as thesubject is continuously exposed to a protective level of the drug andone can provide levels of the drug, which will inhibit response to a 50mg challenge dose of heroin.

[0031] The following examples are offered by way of illustration and notby way of limitation.

EXAMPLES Example 1 General Method of Preparation of NaltrexoneMicroparticles

[0032] The following example is exemplary of the method of preparationgenerally, where the individual conditions are indicated in thefollowing table. The chemical components are prepared as follows.Poly(D,L-lactide) is dissolved in ethyl acetate with stirring. The drugis added to the polymer solution and dissolved with stirring. Poly(vinylalcohol) (“PVA”) is dissolved in sterile water by slowly adding the PVAto the stirred water while heating the sterile water to a temperature of90° C. After complete dissolution of the PVA, the solution is allowed tocool and filtered through a 0.2 μm filter, which is followed by addingethyl acetate to the PVA solution at 3 wt. %.

[0033] The system employed is substantially as described above, wherefor a batch of 15 g, using polymer having a viscosity of 1.07 dL/g and atheoretical drug concentration of 50% (relative to the combined weightof polymer and drug), the tubing employed is 0.5 inches i.d., and thelength of the tubing for the final water extraction is 200 ft.

[0034] The equipment is set up as follows. The organic solution at atemperature of about 20° C. is pumped into the influent tubing at about6 g/min. The PVA solution at about 20° C. is pumped into the influenttubing downstream from the organic solution at a rate of about 65 g/min.An emulsion is formed by continuously feeding this solution into ahomogenizer. The effluent stream is diluted with sterile water at about20° C., which is pumped into the effluent stream at a rate of about 2000g/min through tubing having sufficient length so as to provide anextraction time of about 6 minutes. The resulting microparticles arecollected as particles which pass through a 125-μm sieve and arecollected by a 20-μm sieve. The microparticles are continuously stirredand rinsed with sterile water to prevent premature drying. Afterensuring that there are no more microparticles exiting the homogenizer,the homogenizer is stopped and the microparticles are rinsed withsterile water until there is no further PVA present.

[0035] After rinsing with sterile water the microparticles collected onthe 20-mm sieve are dried under vacuum at room temperature for about 3days. Dried product is obtained after a final sieving of themicroparticles through a 125-μm sieve.

[0036] To reduce any agglomeration, the microparticles may be mixed withor thinly coated with mannitol. The microparticles may then be dispersedin an appropriate vehicle of sterile water comprising 0.5% carboxymethylcellulose, 0.1% Tween 80 and 5.0% mannitol. The volume will be in therange of 1-3.5 mL to obtain satisfactory dispersion and release throughan 18-gauge needle.

[0037] The following table indicates specific parameters for thepreparation of the microparticles and the properties and performance ofthe microparticles in vitro and in vivo. In the in vivo study, dogs wereinjected intramuscularly with an 18-gauge needle with about 2 mL ofsolution containing the microparticles at the weight indicated in thetable. The plasma was monitored for naltrexone at the times indicated.For the in vitro study, microparticles were maintained in 0.01Mphosphate buffer, pH 7.4 at 37° C. and the residual naltrexone in themicroparticles determined at the times indicated. TABLE 1 NaltrexoneNalltrexone loading, loading, Encapsulation Temperature, Polymerinherent Mean particle Lot no. Dog ID target wt % actual wt %efficiency, % ° C. viscosity, dL/g size, μm  92 2062-HM 50 38.3 77 1.0757.76 2067-HM 2073-IM 142 2063-JM 50 42.5 85 1.07 44.36 2066-JM 2070-KM118^(a) 2065-FM 60 49.0 82 22 1.07 39.78 2072-FM 2075-GM

[0038] TABLE 2 Naltrexone in plasma, Naltrexone Microsphere Vehicle,ng/ml) (hrs) Lot no. dose, mg dose mL 1 hr 2 hr 4 hr 8 hr 24 hr 48 hr 92165 430.8 1.8 6.8 2.79 1.82 0.73 0.82 0.81 147 383.8 1.8 6.33 4.14 2.340.64 0.86 202.5 528.7 1.7 9.66 5.28 2.41 0.89 1.13 0.61 142 135 317.61.8 6.22 4.14 2.27 0.67 1.24 1.23 165 388.2 1.8 5.19 3.5 2.33 0.68 0.721.04 191.3 566.5 1.7 17.28 8.79 3.21 1.35 1.02 0.84 118 165 336.7 1.815.56 7.39 1.25 1.81 1.8 133.5 272.4 1.9 7.6 4.04 1.77 0.79 0.71 0.9 225459.2 1.8 13.02 6.62 3.2 1.02 1.41 1.28

[0039] TABLE 3 Naltrexone in plasma, ng/ml Lot no. 3 day 7 day 11 day 14day 18 day 21 day 29 day 35 day  92 1.17 24.95 5.14 3.99 3.27 3.63 1.380.7 0.62 18.04 11.13 7.22 4.87 3.42 1.8 1.55 1.29 40.1 17.71 7.74 4.434.2 1.26 NA 142 1.55 30.35 7.7 2.79 1.74 1.31 0.99 0.86 1.03 23.3 5.822.38 2.1 2.15 1.46 0.87 1.14 32.27 11.98 2.7 37.18 5.74 1.8 NA 118e 2.4445.3 7.17 4.65 1.22 0.48 BQL 1.02 28.4 1.98 0.71 BQL 2.21 35.01 5.632.07 1.44 0.54 BQL

[0040] Lot 98 was above the quantitation level of 0.5 ng/ml out to 140days, while lots 82 and 142 were above the quantitation level up to 49days.

Example 2 Preparation of Buprenorphine (Free-base) Microparticles

[0041] A typical 10 g batch size was prepared as follows:

[0042] A 7% polymer solution was prepared by dissolving 5 g polymer in66.2 g ethyl acetate. To this solution, 5 g of buprenorphine was added.This mixture (the dispersed phase, DP) was stirred until the drugdissolved.

[0043] A solution of 2 wt % poly(vinyl alcohol) was prepared in water.Sufficient ethyl acetate was added to this solution in order that thefinal concentration of ethyl acetate was 2.5 wt %. This solution (thecontinuous phase, CP) is called the CP phase.

[0044] The DP was pumped into a mixer at 27.2 g/min. Using separatetubing, the CP was pumped into the mixer as well at a flow rate of 124g/min. The two solutions were kept separate until immediately beforemixing took place inside the continuous-flow mixer head. Mixing wasperformed at a stir speed of 870 rpm. The emulsion coming out of themixer was extracted using water that was pumped at a rate of 2050 g/minto form a microparticle suspension. The suspension was collected, byhand, across 125-μm and 25-μm sieves. The portion of microparticlescollected on the 25-μm screen was added to a tank of fresh water andstirred for 3 hours under ambient conditions. The microparticles wereagain collected by sieving and the portion obtained on the 25-μm screenwas removed and dried by lyophilization. The final dried powder passedthrough a 125-μm sieve and was characterized with respect to drugcontent and particle size distribution (See Table 4).

Example 3 Preparation of Buprenorphine (Free-base) Microparticles

[0045] A typical 20 g batch size was prepared as follows:

[0046] A 4.1% polymer solution was prepared by dissolving 6.3 g polymerin 146.6 g ethyl acetate. To this solution, 11.6 g of buprenorphine wasadded. This mixture (the dispersed phase, DP) was stirred until the drugdissolved.

[0047] A solution of 1 wt % poly(vinyl alcohol) was prepared in water.Sufficient ethyl acetate was added to this solution in order that thefinal concentration of ethyl acetate was 2.5 wt %. This solution (thecontinuous phase, CP) is called the CP phase.

[0048] The DP was pumped into a mixer at 25.9 g/min. Using separatetubing, the CP was pumped into the mixer as well at a flow rate of 127.2g/min. The two solutions were kept separate until immediately beforemixing took place inside the continuous-flow mixer head. Mixing wasperformed at a stir speed of 726 rpm. The emulsion coming out of themixer was extracted using water that was pumped at a rate of 2038 g/minto form a microparticle suspension. The suspension was collected, byhand, across 125-μm and 25-μm sieves. The portion of microparticlescollected on the 25-μm screen was added to a tank of fresh water andstirred for 3 hours under ambient conditions. The microparticles wereagain collected by sieving and the portion obtained on the 25-μm screenwas removed and dried by lyophilization. The final dried powder passedthrough a 125-μm sieve and was characterized with respect to drugcontent and particle size distribution (See Table 4). TABLE 4Characterization of Buprenorphine Microspheres Drug content,Poly(DL-lactide) IV, wt % Mean particle Lot Number dL/g^(a)buprenorphine size, μm J606-019-00 0.37 21.2 52.8 J606-023-00 0.37 43.157.2 J606-037-00 1.07 44.1 63.1 J606-103-00 1.07 60.9 64.9

[0049] Pharmacokinetics of a single administration in dogs (25 mgbuprenorphine/kg) was measured using microparticles that received about2.5 Mrad gamma-irradiation. TABLE 5 Pharmacokinetic Data in DogsBuprenorphine plasma conc, ng/mL Time J606-019-00 J606-023-00J606-037-00  1 hr 7.23 2.86 4.98  2 hr 10.3  5.80 7.13  4 hr 13.2  3.754.92  8 hr 9.42 2.62 2.58 24 hr 2.22 2.45 2.27 48 hr 3.01 1.85 1.15 72hr 2.54 1.42 0.86 Day 5  1.26 1.22 0.6  Day 6  1.16 0.98 0.66 Day 7 1.03 0.94 0.6  Day 8  1.39 1.45 0.59 Day 12 1.05 2.71 3.37 Day 15 0.964.41 3.02 Day 19 1.00 3.25 3.21 Day 22 1.30 3.01 2.64 Day 26 0.81 3.332.62 Day 30 BQL^(a) 2.33 3.40 Day 32 0.66 1.63 3.25 Day 36 0.68 1.754.04 Day 39 0.58 1.82 3.53 Day 43 BQL 1.30 3.34 Day 46 BQL 1.00 3.35 Day50 BQL 1.36 3.66 Day 53 BQL 1.26 3.74 Day 57 BQL 1.12 4.18 Day 60 BQL1.03 3.53 Day 64 BQL 0.98 4.32

[0050] It is evident from the above results that a long term supply of apartial opiod agonist or opioid antagonist at a physiologicallyeffective concentration can be provided in vivo. In this way, complianceproblems associated with the requirement of taking a pill daily can beavoided. Monitoring to determine whether the subject has taken the dailypill is obviated. The subject is better able to deal with the problem ofsubstance abuse, being aware that the subject has better control in thecase of alcoholism and will not obtain the desired euphoria from heroin.Counseling can be more effectively performed, since the subject will bediscouraged from taking heroin and in the case of alcoholism, will bebetter able to cope with fewer drinks. In this way, subjects will beable to function and fulfill their obligations to their families andsociety.

[0051] All publications and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication or patent application was specificallyand individually indicated to be incorporated by reference.

[0052] The invention now being fully described, it will be apparent toone of ordinary skill in the art that many changes and modifications canbe made thereto without departing from the spirit or scope of theappended claims.

What is claimed is:
 1. A microparticle composition comprising abuprenorphine free base in an amount in the range of 10 to 70 weight %,poly(D,L-lactide) as a excipient, and less than about 3 weight % ethylacetate, capable of providing a physiologically effective level of toreduce the consumption of heroin and/or alcohol when administeredintramuscularly in a mammal over a period of about 28 days, at least 90weight % of said microparticle composition comprising microparticleshaving a diameter in the range of 20 to 125 μm.
 2. A microparticlecomposition according to claim 1, wherein said buprenorphine is presentin an amount in the range of 15 to 50 weight %, said poly(D,L-lactide)has an inherent viscosity in the range of about 0.3 to 0.4 dL/g and saidethyl acetate is present in from about 0.1 to 3 weight %.
 3. Amicroparticle composition according to claim 1, wherein saidbuprenorphine is present in an amount in the range of 30 to 65 weight %,said poly(D,L-lactide) has an inherent viscosity in the range of about1.0 to 1.1 dL/g and said ethyl acetate is present in from about 0.1 to 3weight %.
 4. A microparticle composition according to claim 1, whereinsaid poly(D,L-lactide) is a mixture of poly(D,L-lactide)s of differinginherent viscosity.
 5. A microparticle composition according to claim 1,wherein said composition is a mixture of microparticles which differ inat least one of weight % of buprenorphine or poly(D,L-lactide)s ofdiffering inherent viscosity.
 6. A microparticle composition accordingto claim 1, wherein said microparticles are prepared by introducing asolution of said buprenorphine and poly(D,L-lactide) in ethyl acetateinto an aqueous ethyl acetate containing solution of poly(vinyl alcohol)to form an emulsion and adding said emulsion to water to extract ethylacetate to form microparticles, and isolating the resultingmicroparticles.
 7. A formulation for injection comprising amicroparticle composition according to claim 1, carboxymethyl cellulose,Tween and mannitol.
 8. A method for reducing the consumption of heroinand/or alcohol by a subject abusing at least one of heroin and alcohol,said method comprising: administering intramuscularly an effective doseof a microparticle composition according to claim 1 in an amount toinhibit the consumption of heroin and alcohol, whereby the consumptionof heroin and/or alcohol is reduced.
 9. A method for reducing theconsumption of heroin and alcohol by a subject abusing at least one ofheroin and alcohol, said method comprising: administering an effectivedose of a microparticle composition according to claim 1, whichcomposition continues to release said buprenorphine for a period greaterthan 28 days at at least an effective dose; prior to the level of saidbuprenorphine falling below an effective dose, administering a seconddose of said microparticle composition, whereby the combination of saidoriginal effective dose and said second dose provide an effective doseof said buprenorphine for a second period of at least an additional 28days; and repeating said adminstration to have said buprenorphine beingreleased from both a prior adminstration of said microparticlecomposition and the lately administered microparticle composition tomaintain said effective dose of said buprenorphine.
 10. The methodaccording to claim 9, wherein at least one of said period and saidsecond period is about 60 days.